Steroid hormones regulate many aspects of mammalian physiology. Steroids pass through membranes and bind to nuclear receptor/transcription factors, initiating a change in gene transcription. Particularly in the nervous system, steroids also exert effects that are too rapid to be attributed to this mechanism. Recently, my laboratory discovered a novel mode of steroid action: sulfated steroids are detected by neurons residing in the vomeronasal organ, which provide sensory input to the accessory olfactory system. These sensory neurons express several hundred different types of G protein-coupled receptors, and different neurons detect different sulfated steroids. Sulfated steroids are present in natural bodily secretions, such as urine, and represent a prime candidate for organizing mammalian social behavior. In mice, behavioral or physiological responses mediated by the accessory olfactory system frequently involve integration of multiple cues; in particular, there are several examples in which male-derived stimuli act in opposition with female-derived stimuli, and the integration of these cues leads to a single behavioral response. We hypothesize that these behaviors arise as a direct consequence of the neuronal circuitry that processes sensory data about sulfated steroids. To test this hypothesis, we propose both electrophysiological and behavioral experiments that will elucidate the functions of this circuitry in analyze complex steroidal blends. In aim 1, we will determine how mitral cells of the accessory olfactory bulb encode information about individual sulfated steroids, and test how circuit processing changes the representation inherited from the sensory neurons. In aim 2, we will examine the role of male and female steroidal cues in mixture suppression, a likely physiological correlate of male/female opponent behavioral processes. In aim 3, we will examine the role of olfactory-detected sulfated steroids in estrous cycle suppression, focusing in particular on the role of glucocorticoids. In aim 4, we will examine the role of sulfated steroids in protecting against pregnancy block triggered by the urine of strange males. These aims will illuminate the novel role of steroids in the olfactory regulation of mammalian reproductive behaviors. PUBLIC HEALTH RELEVANCE: A better understanding of steroid effects in the nervous system offers hope for treatment of stress, anxiety, and mood disorders, as well as to shed light on sex differences in neuronal development. Most experiments on steroid effects are performed in rodents, but interpretation of the results is complicated by differences between rodents and humans. Olfactory detection may represent a major, previously-unrecognized mechanism for steroid action in mice; understanding this phenomenon will provide critical new insights for interpreting studies that alter the steroid milieu.